(The extension study was terminated early after the results of the core study showed the study did not meet primary endpoint; confirmed disability progression)

Sponsor:

Novartis Pharmaceuticals

ClinicalTrials.gov Identifier:

NCT00731692

First Posted: August 11, 2008

Last Update Posted: June 14, 2017

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The purpose of this study is to evaluate whether FTY720 is effective in delaying MS disability progression compared to placebo in patients with PPMS. This was an open-label, single-arm extension study to a double-blind, randomized multicenter, placebo-controlled, parallel-group core study. The core study completed and eligible patients enrolled into the extension study at the next scheduled or unscheduled core study visit. All patients, regardless of their treatment in the core study, received fingolimod 0.5 mg in the extension study. The extension study was terminated early after the results of the core study became available showing that the study did not meet its primary endpoint which was defined as confirmed disability progression in this population

Kaplan-Meier Estimate of the Risk of 3-month Confirmed Disability Progression Based on Composite Endpoint [ Time Frame: up to 36 months after the last patient was randomized ]

3-month sustained increase from Baseline in EDSS (at least 1 point increase from Baseline for patients with a Baseline value of 5 or less or at least 0.5 point increase from Baseline for patients with a Baseline value of 5.5 or more) or 3-month sustained increase of at least 20% from BL in the time taken to complete the timed 25-foot walk test (25' TWT); or 3-month sustained increase of at least 20% from BL in the time taken to complete the 9-HPT. The 25' TWT is a quantitative measure of lower extremity function. The EDSS is a scale assessing neurologic impairment, including a series of scores in each of 8 functional systems: Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel and Bladder, Cerebral and Other functions. The score ranges from 0 (normal) to 10 (death due to MS)). The 9-hole peg test (9-HPT) is a quantitative measure of upper extremity (arm and hand) function.

Secondary Outcome Measures:

Kaplan-Meier Estimate of the Risk of 3- Month Confirmed Disability Progression Based on Expanded Disability Status Scale (EDSS) [ Time Frame: up to 36 months after the last patient was randomized ]

The Expanded Disability Status Scale (EDSS) is a scale for assessing neurologic impairment in MS (Kurtzke 1983) and includes a series of scores in each of 8 functional systems and the EDSS steps (ranging from 0 (normal) to 10 (death due to MS)). The functional systems are Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel and Bladder, Cerebral and Other functions. Fatigue is not included in the Cerebral score of the EDSS. The score ranges from 0 (normal) to 10 (death due to MS)

The percent change from Baseline in brain volume was analyzed using a random coefficients model. The model included: 1) fixed effects: treatment and region and 2) continuous covariates: time, number of Gd enhancing lesions at Baseline, Baseline T2 volume, and normalized brain volume at Baseline. Time as a continuous covariate allowed for the estimation of different slopes and intercepts among treatment groups.

Kaplan Meier Estimate -Percentage of Participants With 3- Month Confirmed Disability Progression Based on 9-HPT. [ Time Frame: up to 36 months after the last patient was randomized ]

The 9-HPT is a quantitative measure of upper extremity (arm and hand) function designed and validated for evaluation of MS patients. N= Total number of patients included in the analysis

Kaplan Meier Estimate -Percentage of Participants With 3- Month Confirmed Disability Progression Based on 25' TWT. [ Time Frame: up to 36 months after the last patient was randomized ]

The 25' TWT is a quantitative measure of lower extremity function designed and validated for evaluation of MS patients. N= Total number of patients included in the analysis

Number of New/Enlarging T2 Lesions Per Year Measured From Baseline to Month 36 [ Time Frame: Baseline to 36 months ]

Inflammatory disease, as measured by number of new or newly-enlarging T2 lesions, was assessed by Magnetic resonance Imaging (MRI) scanning of the brain and full spinal cord. N= Total number of patients included in the analysis

Number of Gd-enhancing Lesions at Month 36 [ Time Frame: Baseline to 36 months ]

Inflammatory disease, as measured by number of T1 Gd-enhancing lesions, was assessed by MRI scanning of the brain and full spinal cord. N= Total number of patients included in the analysis

Percent Change in Total T2 Lesion Volume From Baseline to Month 36 [ Time Frame: Baseline to month 36 ]

Inflammatory disease as measured by percent change in total T2 lesion volume (mm3) was assessed by MRI. N= Total number of patients included in the analysis

The quality of life scale contains 22 items. Each item will be given a score of 1 or 0. A score of 1 (or 0) indicates the presence (or absence) of the symptom or adverse quality of life. All 22 item scores will be summed to obtain a total score ranging from 0 (good) to 22 (poor), which is the PRIMUS QoL scale score

The activities subscale of PRIMUS contains 15 items and each item is given a score of 0 (able to do on own without difficulties), 1 (able to do on own with difficulties), or 2 (unable to do on own). All 15 items were summed to obtain a total score ranging from 0 (good) to 30 (poor).

Unidimensional Fatigue Impact Scale (U-FIS), contains 22 patient-reported items that assess the impact of fatigue on cognitive, physical, and psychosocial functioning. Responses formed a single unidimensional scale measuring fatigue impact. The U-FIS was calculated and analyzed according to the U-FIS scoring manual. The U-FIS scale contains 22 items with 5 possible outcomes for each item. Two response categories (about half the time and a lot of the time) were combined into 1 category to obtain 4 possible outcomes: 0 (never), 1 (a little of the time), 2 (about half the time/a lot of the time), and 3 (all the time). The 22 condensed item scores were summed to obtain a total score ranging from 0 (no fatigue) to 66 (severe fatigue impact).

Change From Baseline in European Quality of Life - 5 Dimensions (EQ-5D Score) [ Time Frame: Baseline, 36 months ]

EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self care, usual activities, pain and discomfort, and anxiety and depression; 1 indicates better health state (no problems); 3 indicates worst health state (confined to bed). Scoring formula developed by EuroQoL Group assigns a utility value for each domain in the profile. Score is transformed and results in a total score range -0.594 to 1.000; higher score indicates a better health state.

The Multiple Sclerosis Walking Scaleis a patient reported measure of walking quality (Hobart et al 2003), consisting of 12 items asking patients to rate the impact of MS upon their walking ability. Responses were captured on a 3-point scale ranging from 1 (Not at all) to 3 (A lot) for items 1 to 3 and on a 5-point scale ranging from 1 (not limited) to 5 (extremely) for items 4 to 12. All 12 item scores were summed to obtain a total score ranging from 12 (good) to 54 (poor) which is the MSWS-12 scale score. The total score was transformed to a 0 to 100 scale score. The MSWS-12 scale score will be transformed to a 0-100 scale score before any summaries or statistical analyses are performed. The transformed score is obtained by subtracting 12 and divided by 42 and multiplying by 100 (i.e., transformed scale score = (raw scale score- 12)/42*100).

Blood Concentrations of Fingolimod and Fingolimod-phosphate [ Time Frame: Month 3 up to 36 months ]

Concentrations of fingolimod and fingolimod-phosphate in whole blood were determined by validated liquid chromatography methods with tandem mass spectrometry. The lower limits of quantification were 0.08 ng/ml for fingolimod and 0.1 ng/ml for fingolimod-phosphate.

Venous blood samples were collected for the analysis.

Change in MSFC Z-score and Subscale Scores From Baseline to Month 36 [ Time Frame: Baseline to Month 36 ]

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Ages Eligible for Study:

25 Years to 65 Years (Adult)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

General

sign written informed consent prior to participating in the study

25 through 65 years of age inclusive

females of childbearing potential must:

have a negative pregnancy test at Baseline (prior to randomization) and

use simultaneously two forms of effective contraception during the treatment and 3-months after discontinuation of study medication

evidence of clinical disability progression in the 2 years prior to Screening

disability status at Screening

EDSS score of 3.5-6.0 inclusive

pyramidal functional system score of 2 or more

25'TWT less than 30 seconds

Extension study Inclusion criteria

Patients initially randomized to fingolimod 1.25 mg or placebo as part of the first study cohort, were to have completed at least 3 years on study drug treatment at the time of extension study initiation.

Patients initially randomized to fingolimod 0.5 mg or placebo as part of the second study cohort, were to have continued on study drug treatment until such time as the last ongoing patient enrolled in the study had reached 3 years in study

Exclusion Criteria:

PPMS specific:

History of relapses/attacks

Progressive neurological disorder other than PPMS

Pure cerebellar syndrome or pure visual progressive syndrome or pure

cognitive progressive syndrome

Presence of spinal cord compression at screening MRI

Relevant history of vitamin B12 deficit

Evidence of syphilis or borreliosis at Screening

Cardiovascular conditions:

Myocardial infarction within the past 6 months or current unstable ischemic heart disease

History of angina pectoris due to coronary spasm or history of Raynaud's phenomenon

Severe cardiac failure or cardiac arrest

History of symptomatic bradycardia

Resting pulse <55 bpm pre-dose

History of sick sinus syndrome or sino-atrial heart block

History or presence of second and third degree AV block or an increase QT interval (QTc>440 ms)

Arrythmia requiring treatment with class III antiarrythmic drugs

History of positive tilt test from workout of vasovagal syncope

Hypertension, not controlled with medication

Pulmonary:

Severe respiratory disease or pulmonary fibrosis

TB

Abnormal X-ray, suggestive of active pulmonary disease

Abnormal PFT: <70% of predicted for FEV1 and FVC; <60% for DLCO

Patients receiving chronic (daily) therapies for asthma

Hepatic:

Known history of alcohol abuse, chronic liver or biliary disease

Total or conjugated Brb >ULN, unless in context of Gilbert's syndrome

AP >1.5xULN; ALT/AST >2xULN; GGT>3xULN

Other:

History of chronic disease of the immune system other than MS

Malignancy (other than successfully treated SCC or BCC)

Diabetes Mellitus

Macular Edema present at screening

HIV, Hepatitis C or B, other active infection

History of total lymphoid irradiation or bone marrow transplantation

Serum creatinine >1.7 mg/dl

WBC <3500 cells/mm3

Lymphocyte count <800 cells/mm3

History of substance abuse or any other factor that may interfere with subject ability to cooperate and comply with the study procedures

Unable to undergo MRI scans

Participation in any therapeutical clinical research study in the 6 months prior to randomization

Pregnant or lactating women

Drugs requiring wash-out period:

3 months:

Systemic corticosteroids or ACTH

INF-beta

6 months:

Immunosuppressive medication

Immunoglobulins

Monoclonal antibodies

Drugs that exclude participation in the study:

Cladribine

Cyclophosphamide

Mitoxantrone (except: patients who received a cumulative dose of no more than 60mg/m2 more than 5 years ago could enter the study)

Extension study Exclusion criteria

-Patients were not eligible for enrollment in the extension study if they had any of the following key exclusion criteria at the extension study Baseline visit: active chronic immune system disease other than MS (or stable disease treated with immune therapy); known immunodeficiency syndrome; active infection; uncontrolled diabetes mellitus; macularedema; treatment with Class Ia or III antiarrhythmic drugs; any of the specified cardiac, pulmonary, or hepatic conditions; or any medically unstable condition

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00731692

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com